Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEDUI2J)

• DOT Name: Coiled-coil domain-containing protein 88B (CCDC88B)
• Synonyms: Brain leucine zipper domain-containing protein; Gipie; Hook-related protein 3; HkRP3
• Gene Name: CCDC88B
• Related Disease:
  Autoimmune disease
  Autoimmune disease, susceptibility to, 6
  Colitis
  Crohn disease
  Inflammatory bowel disease
  Leprosy
  Primary biliary cholangitis
  Sclerosing cholangitis
  STAT3-related early-onset multisystem autoimmune disease
  Ulcerative colitis
  Immune system disorder
  Basal cell carcinoma
  Basal cell neoplasm
• UniProt ID: CC88B_HUMAN
• Pfam ID: PF19047
• Sequence:
  MEGGKGPRLRDFLSGSLATWALGLAGLVGEAEDSEGEEEEEEEEPPLWLEKRFLRLSDGA
  LLLRVLGIIAPSSRGGPRMLRGLDGPAAWRVWNLNHLWGRLRDFYQEELQLLILSPPPDL
  QTLGFDPLSEEAVEQLEGVLRLLLGASVQCEHRELFIRHIQGLSLEVQSELAAAIQEVTQ
  PGAGVVLALSGPDPGELAPAELEMLSRSLMGTLSKLARERDLGAQRLAELLLEREPLCLR
  PEAPSRAPAEGPSHHLALQLANAKAQLRRLRQELEEKAELLLDSQAEVQGLEAEIRRLRQ
  EAQALSGQAKRAELYREEAEALRERAGRLPRLQEELRRCRERLQAAEAYKSQLEEERVLS
  GVLEASKALLEEQLEAARERCARLHETQRENLLLRTRLGEAHAELDSLRHQVDQLAEENV
  ELELELQRSLEPPPGSPGEAPLAGAAPSLQDEVREAEAGRLRTLERENRELRGLLQVLQG
  QPGGQHPLLEAPREDPVLPVLEEAPQTPVAFDHSPQGLVQKARDGGPQALDLAPPALDSV
  LEASAECPQAPDSDPQEAESPLQAAAMDPQASDWSPQESGSPVETQESPEKAGRRSSLQS
  PASVAPPQGPGTKIQAPQLLGGETEGREAPQGELVPEAWGLRQEGPEHKPGPSEPSSVQL
  EEQEGPNQGLDLATGQAEAREHDQRLEGTVRDPAWQKPQQKSEGALEVQVWEGPIPGESL
  ASGVAEQEALREEVAQLRRKAEALGDELEAQARKLEAQNTEAARLSKELAQARRAEAEAH
  REAEAQAWEQARLREAVEAAGQELESASQEREALVEALAAAGRERRQWEREGSRLRAQSE
  AAEERMQVLESEGRQHLEEAERERREKEALQAELEKAVVRGKELGDRLEHLQRELEQAAL
  ERQEFLREKESQHQRYQGLEQRLEAELQAAATSKEEALMELKTRALQLEEELFQLRQGPA
  GLGPKKRAEPQLVETQNVRLIEVERSNAMLVAEKAALQGQLQHLEGQLGSLQGRAQELLL
  QSQRAQEHSSRLQAEKSVLEIQGQELHRKLEVLEEEVRAARQSQEETRGQQQALLRDHKA
  LAQLQRRQEAELEGLLVRHRDLKANMRALELAHRELQGRHEQLQAQRASVEAQEVALLAE
  RERLMQDGHRQRGLEEELRRLQSEHDRAQMLLAELSRERGELQGERGELRGRLARLELER
  AQLEMQSQQLRESNQQLDLSACRLTTQCELLTQLRSAQEEENRQLLAEVQALSRENRELL
  ERSLESRDHLHREQREYLDQLNALRREKQKLVEKIMDQYRVLEPVPLPRTKKGSWLADKV
  KRLMRPRREGGPPGGLRLGADGAGSTESLGGPPETELPEGREADGTGSPSPAPMRRAQSS
  LCLRDETLAGGQRRKLSSRFPVGRSSESFSPGDTPRQRFRQRHPGPLGAPVSHSKGPGVG
  WENSAETLQEHETDANREGPEVQEPEKRPLTPSLSQ
• Function: Acts as a positive regulator of T-cell maturation and inflammatory function. Required for several functions of T-cells, in both the CD4(+) and the CD8(+) compartments and this includes expression of cell surface markers of activation, proliferation, and cytokine production in response to specific or non-specific stimulation. Enhances NK cell cytotoxicity by positively regulating polarization of microtubule-organizing center (MTOC) to cytotoxic synapse, lytic granule transport along microtubules, and dynein-mediated clustering to MTOC. Interacts with HSPA5 and stabilizes the interaction between HSPA5 and ERN1, leading to suppression of ERN1-induced JNK activation and endoplasmic reticulum stress-induced apoptosis.
• Tissue Specificity: Expressed in endothelium (at protein level) . Expressed in NK cells (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[1]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[1]
Colitis	DISAF7DD	Strong	Biomarker	[2]
Crohn disease	DIS2C5Q8	Strong	Altered Expression	[2]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[2]
Leprosy	DISAA4UI	Strong	Biomarker	[3]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[4]
Sclerosing cholangitis	DIS7GZNB	Strong	Genetic Variation	[5]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[1]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[2]
Immune system disorder	DISAEGPH	moderate	Genetic Variation	[6]
Basal cell carcinoma	DIS7PYN3	Limited	Genetic Variation	[7]
Basal cell neoplasm	DIS37IXW	Limited	Genetic Variation	[7]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Coiled-coil domain-containing protein 88B (CCDC88B).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Coiled-coil domain-containing protein 88B (CCDC88B).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Coiled-coil domain-containing protein 88B (CCDC88B).	[17]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Coiled-coil domain-containing protein 88B (CCDC88B).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Coiled-coil domain-containing protein 88B (CCDC88B).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Coiled-coil domain-containing protein 88B (CCDC88B).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Coiled-coil domain-containing protein 88B (CCDC88B).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Coiled-coil domain-containing protein 88B (CCDC88B).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Coiled-coil domain-containing protein 88B (CCDC88B).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Coiled-coil domain-containing protein 88B (CCDC88B).	[16]

References

• [1] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [2] CCDC88B is required for pathogenesis of inflammatory bowel disease.Nat Commun. 2017 Oct 13;8(1):932. doi: 10.1038/s41467-017-01381-y.
• [3] Discovery of six new susceptibility loci and analysis of pleiotropic effects in leprosy.Nat Genet. 2015 Mar;47(3):267-71. doi: 10.1038/ng.3212. Epub 2015 Feb 2.
• [4] International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.Nat Commun. 2015 Sep 22;6:8019. doi: 10.1038/ncomms9019.
• [5] Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):269-273. doi: 10.1038/ng.3745. Epub 2016 Dec 19.
• [6] CCDC88B is a novel regulator of maturation and effector functions of T cells during pathological inflammation.J Exp Med. 2014 Dec 15;211(13):2519-35. doi: 10.1084/jem.20140455. Epub 2014 Nov 17.
• [7] Combined analysis of keratinocyte cancers identifies novel genome-wide loci.Hum Mol Genet. 2019 Sep 15;28(18):3148-3160. doi: 10.1093/hmg/ddz121.
• [8] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [9] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [10] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [14] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.